graduate work, he studied crystal structures of Michael G. Rossmann (1930-2019), organic compounds with J. Monteath Robertson at pioneer in macromolecular and virus the University of Glasgow. Following his graduate crystallography: scientist and friend studies he was a postdoctoral fellow with William N. Lipscomb at the University of Minnesota, USA, pursuing structures of relatively complicated organic crystals. In his work at Minnesota, Michael wrote computer programs for crystal structure analysis, taking advantage of the new digital computers that would revolutionize the practice of crystallography. In a lecture by Dorothy Hodgkin at the Fourth IUCr Congress in Montreal in 1957, Michael learned about exciting work on the structure determination of hemoglobin by Max Perutz at Cambridge University. Michael wrote to Max and was given an offer to join the hemoglobin structure determination team. 2. First Protein Structures at Cambridge: hemoglobin with Max Perutz Michael Rossmann with a virus model in 2018. Michael worked closely with Max Perutz and was (photo courtesy of Roger Castells Graells) instrumental in elucidating the hemoglobin Michael George Rossmann, who made monumental structure by writing the computer programs contributions to science, passed away peacefully in required to solve and analyze these first structures, West Lafayette, Indiana, USA, on 14 May 2019 at the and by calculating the Fourier maps that gave rise to age of 88, following a courageous five-year battle with the hemoglobin structure. Max had been pursuing cancer. Michael was born in Frankfurt, Germany, on 30 the crystal structure of hemoglobin since the late July 1930. As a young boy, he emigrated to England 1930s and was a protégé of Sir Lawrence Bragg, one with his mother just as World War II ignited. The of the giants of crystallography who had helped to eminent crystallographer Dame Kathleen Lonsdale create the field of X-ray crystallography with his helped him gain admittance to a Quaker School for his father, Sir William Bragg. When Michael arrived at school studies (Sir John Meurig Thomas, personal Cambridge he began to analyze the X-ray diffraction communication) and also sparked his interest in data that Max and Ann Cullis had collected for the crystallography. Michael was a highly innovative and native hemoglobin crystals and multiple heavy-atom energetic person, well known for his intensity, derivatives. persistence and focus in pursuing his research goals. He invented methods and created computer Michael was a towering figure in crystallography as a algorithms for reliable phasing using heavy- atom highly distinguished faculty member at Purdue isomorphous replacement and the practical University for 55 years. Michael made many seminal determination of protein structures. contributions to crystallography in a career that Whileprocessing and analyzing the existing spanned the entirety of structural biology, beginning in heavy-atom derivative datasets, he developed the the 1950s at Cambridge where the first protein difference Patterson map using squared difference structures were determined in the laboratories of Max coefficients Perutz (hemoglobin, 1960) and John Kendrew 2 (|Fheavy| |Fnative|) t​ o assist in locating the relative (myoglobin, 1958). Michael's work was central in ​ ​ − ​ ​ ​ establishing and defining the field of structural biology, positions of heavy atoms in the isomorphous which has described the structures of an amazing array datasets (Rossmann, 1960). Michael also applied of macromolecules and macromolecular assemblies, similar considerations to locating heavy atoms using contributing to our understanding the basis of health anomalous dispersion (Rossmann, 1961) and with and disease at the molecular level, and facilitating the David Blow developed the single isomorphous discovery of many drugs. replacement method (Blow & Rossmann, 1961) and mathematical representations of combining phase 1. Education in crystallography with J. Monteath information from multiple sources (Rossmann & Robertson and William N. Lipscomb Blow, 1961). By 1959, Michael had computed a 5.5 Michael had an enormous impact on developing Å resolution electron- density map for hemoglobin methodology for the determination of macromolecular that permitted a trace of the overall fold of this crystal structures. His grasp of mathematics was always predominantly helical protein and revealed its a strength, as he continually developed methods that three-dimensional relationship with myoglobin would become part of the standard repertoire of (Perutz et al., 1960). macromolecular crystallographic tools. Michael 3. Molecular replacement has become the obtained undergraduate degrees in mathematics and most common method for solving macromolecular physics at the University of London. For his crystal structures During his extraordinarily productive time at Cambridge, Michael also proposed and created the ​ the process more convenient. foundations for the molecular replacement method, 4. Conserved nucleotide-binding fold in glycolytic which became the predominant approach for enzymes: the Rossmann fold and revolutionary solving three-dimensional structures of proteins and concepts in molecular evolution other large biological assemblies such as complex Michael moved to Purdue University in 1964 to enzymes and viruses. Michael had been fascinated develop his own research program and apply his with what he learned from conversations with other innovative methods to solve important biological scientists at Cambridge, often during afternoon tea. structures. By 1971 he had determined the structure For example, Crick and Watson had hypothesized of the largest protein to date, the enzyme lactate that viruses would contain many identical protein dehydrogenase (Adams et al., 1970). Within a few subunits based on considerations of their limited years he solved another related glycolytic enzyme, genomic capacity (Crick & Watson, 1956). Michael lobster glyceraldehyde-3-phosphate dehydrogenase, thought that the recurrence of biological structure and showed unexpectedly that the nucleotide in different environments, whether in a structure cofactor- binging portion of the structures had highly with multiple subunits (oligomeric enzymes, viruses similar folds. Based on these observations he etc.) or in different crystals, would provide ​ suggested that the architecture of proteins evolved information to help in phasing crystal structures. in the same way as the anatomy of animals (Buehner The monumental paper that Michael wrote et al., 1973; Rossmann et al., 1974). This conserved together with David Blow (Rossmann & Blow, 1962) part of protein anatomy is called the 'Rossmann fold' presented the rotation function as a method for to recognize Michael's ingenious new idea. He had demonstrating the presence of rotational initially thought along these lines at Cambridge: non-crystallographic symmetry within a when solving the structure of hemoglobin, a protein crystallographic asymmetric unit and determining that carries oxygen in red blood cells, Michael saw relative orientations. Walter Hoppe (Hoppe, 1957) that the two protein chains of hemoglobin had had also hinted at a convolution of a similar type to strong three-dimensional resemblance to each other find the orientation of known molecular fragments despite having significant sequence differences, and and these ideas were implemented by Robert Huber also to myoglobin, which carries oxygen in muscle (Huber, 1965). Michael developed the rotation tissues. Although these concepts are very well function based on the realization that the Patterson accepted now, they were revolutionary when function would produce multiple "peaks" where suggested, and were often greeted with resistance. vector sets corresponding to the different orientations of the repeating units were coincident. 5. Passion for viruses: technology and a plant virus He demonstrated its utility by detecting the relative structure orientation of the α and β chains in horse A driving force behind Michael's interest in hemoglobin crystals. Later he and others would pursuing more and more complicated biological develop methods for locating the position of objects structures and in technology development was his in crystals, so-called translation functions. He went passion to study virus structure. Michael on to champion these ideas, while along the way subsequently pioneered the structure solution of determining the structures of many crucial enzymes entire viruses in atomic detail, requiring considerable and viruses. advances in technology to handle the larger unit cells and massive amounts of crystallographic data. Currently, the molecular replacement method is the Following the publication of the tomato bushy stunt most common approach used for solving new virus structure (Harrison et al., 1978) from Stephen macromolecular structures, accounting for some Harrison's group in 1978, Michael reported the 85%+ of all new PDB structure depositions and the structure of Southern bean mosaic virus majority of all 150 000+ known structures. (Abad-Zapatero et al., 1980), and the surprising Molecular replacement is most frequently used to revelation that the coat protein structures of these determine the orientation and location of related two plant viruses shared a common protein fold, an structures in new crystals. The search model can be eight-stranded β-barrel also known as a 'jelly roll' the same as the new structure, or a homolog with fold. This work required the development